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      Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes

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          Abstract

          Aim

          Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.

          Methods and results

          We sequenced known and putative HCM genes in a new large prospective HCM cohort ( n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients ( n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence.

          Conclusion

          We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.

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          Most cited references 12

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          Hypertrophic cardiomyopathy: a systematic review.

           Barry J Maron (2002)
          Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum. To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM. Systematic analysis of the relevant HCM literature, accessed through MEDLINE (1966-2000), bibliographies, and interactions with investigators. Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies. Hypertrophic cardiomyopathy is a relatively common genetic cardiac disease (1:500 in the general population) that is heterogeneous with respect to disease-causing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographic identification of otherwise unexplained left ventricular wall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke. Treatment strategies depend on appropriate patient selection, including drug treatment for exertional dyspnea (beta-blockers, verapamil, disopyramide) and the septal myotomy-myectomy operation, which is the standard of care for severe refractory symptoms associated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator. Substantial understanding has evolved regarding the epidemiology and clinical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.
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            Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

            Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years.
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              Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.

              Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                07 December 2017
                11 January 2017
                11 January 2017
                : 38
                : 46 , Focus Issue on Cardiomyopathies
                : 3461-3468
                Affiliations
                [1 ]NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Sydney Street, London SW3 6NP, UK
                [2 ]Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK
                [3 ]Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
                [4 ]Radcliffe Department of Medicine, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
                [5 ]National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, 169609 Singapore, Singapore
                [6 ]NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
                [7 ]Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, 65 Lansdowne Street, Cambridge, MA 02139, USA
                [8 ]Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
                [9 ]The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
                [10 ]Cardiovascular Magnetic Resonance Imaging and Genetics, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
                [11 ]Division of Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, 8 College Road, 169857 Singapore, Singapore
                Author notes
                Corresponding author. Tel: (65) 6601 3290, Fax: (65) 6221 2534, Email: stuart.cook@ 123456imperial.ac.uk

                See page 3469 for the editorial comment on this article (doi: [Related article:]10.1093/eurheartj/ehx024)

                Article
                ehw603
                10.1093/eurheartj/ehw603
                5837460
                28082330
                © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 8
                Product
                Funding
                Funded by: Imperial College London 10.13039/501100000761
                Funded by: Wellcome Trust 10.13039/100004440
                Award ID: 107469/Z/15/Z, 090532/Z/09/Z
                Funded by: Fondation Leducq 10.13039/501100001674
                Funded by: Medical Research Council 10.13039/501100000265
                Funded by: British Heart Foundation 10.13039/501100000274
                Award ID: SP/10/10/28431
                Funded by: National Medical Research Council 10.13039/501100001349
                Funded by: NMRC 10.13039/100007680
                Award ID: NMRC/STaR/0011/2012
                Funded by: Wellcome Trust 10.13039/100004440
                Categories
                Basic Science
                Hypertension

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